Glycoside derivatives of epipodophyllotoxin, for example, etoposide and teniposide, are valuable anti-neoplastic drugs. They have applications in the treatment of numerous cancers, including small-cell lung cancer and testicular cancer [Clin. Pharmacy, 2, 112 (1983)]. High efficacy and relatively low toxicity are other desirable characteristics of special interest in these drugs. Unless indicated otherwise, all references cited herein are incorporated by reference in their entirety.
The above materials are generally prepared using podophyllotoxin as a starting material. Podophyllotoxin is a component of extracts from the roots and rhizomes of the medicinal plants Podophyllum emodi Wall and Podophyllum peltatum L. Conversion of podophyllotoxin to etoposide or teniposide is a complicated process, involving many chemical steps and requiring several corrosive reagents. The use of these reagents presents not only handling and equipment problems but also causes environmental problems.
Disclosed processes for the conversion of podophyllotoxin to etoposide are based on the reaction of podophyllotoxin with gaseous hydrogen bromide. In the process described in Israeli Patent No. 26522, a suspension of podophyllotoxin in ethylene chloridediethyl ether is treated with a large excess of hydrogen bromide gas. The reaction intermediate product, 1-bromo-4'-demethylepipodophyllotoxin, is isolated by first vacuum distilling this highly corrosive solvent mixture and then precipitating the product from the resinous residue with acetone. The 1-bromo-4'-demethylepipodophyllotoxin is then hydrolyzed to give 4'-demethylepipodophyllotoxin. Reaction of 4'-demethylepipodophyllotoxin with the highly toxic benzyl chloroformate results in the formation of 4'-demethyl-4'-benzyloxycarbonyl epipodophyllotoxin (see, e.g., British Patent 1,205,966). As described in Swiss Patent 514578 4'-demethyl-4'-benzyloxycarbonyl epipodophyllotoxin is condensed with 2,3-diacetyl-4,6-O-ethylidene-D-glucopyranose in the presence of boron trifluoride etherate to give the 2",3"-diacetyl-4' -benzoxycarbonyl derivative of etoposide. Finally, etoposide is obtained by removing the acetyl groups with methanol in the presence of zinc acetate and removing the carbobenzoxy group by catalytic hydrogenolysis.
This complicated process was simplified by the inventors of U.S. Pat. No. 4,900,814 by converting 1-bromo-4'-demethylepipodophyllotoxin to the corresponding 1-bromo-4'-demethyl-4'-acetylepipodophyllotoxin derivative, followed by hydrolysis to yield 4'-demethyl-4'acetylepipodophyllotoxin. Reaction with 2,3-diacetyl-4,6-O-ethylidene-1-tributylstannyloxy-D-gluco-pyranose gives, in a highly stereospecific reaction, etoposide triacetate from which etoposide may be obtained in a single transesterification reaction.
U.S. Pat. No. 4,900,814, discloses an example of a process for the preparation of etoposide which comprises the steps described in the following numbered paragraphs:
(1) Preparation of 4'-demethyl-4'-acetylepipodophyllotoxin by: PA1 (2) Preparation of beta-etoposide triacetate by condensing 4'-demethyl-4'-acetylepipodophyllotoxin with 4,6-ethylidene-2,3-diacetyl-1-tri(n-butyl)-stannyloxyglucopyranoside in the presence of a Lewis acid catalyst. The resulting product is a mixture of alpha- and beta-etoposide triacetate, which may be subjected to column chromatography to yield the substantially pure beta isomer, or this purification step may be left until later; and PA1 (3) Preparation of etoposide by solvolysis of the etoposide triacetate by reacting it with a lower alkanol in the presence of a transesterification catalyst. This yields a reaction mixture containing etoposide, along with a number of impurities. Pure etoposide is isolated through column chromatography, and the impurities are discarded.
(i) reacting podophyllotoxin with hydrogen bromide gas in methylene chloride-diethyl ester mixed solvent to yield 1-bromo-4'-demethylepipodophyllotoxin and PA2 (ii) reacting the 1-bromo-4'-demethylepipodophyllotoxin with an acetylating agent in the presence of an acid acceptor group, for example, pyridine, to yield 1-bromo-4'-demethyl-4'-acetylepipodophyllotoxin, which is then hydrolyzed to 4'-demethyl-4'-acetylepipodophyllotoxin;